Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
  • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
  • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
  • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
  • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
  • C07D263/57—Aryl or substituted aryl radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to a pharmaceutical composition containing a benzoxa condensed ring compound, and more specifically, it relates to a pharmaceutical composition containing a benzoxazole or 2,3-dihydrobenzofuran compound, which is useful for inhibiting the action of Acyl-Coenzyme A: Cholesterol Acyltransferase (i.e., "ACAT" herein below). Furthermore, the present invention relates to a process for producing the above-mentioned compound and a novel compound belonging to the category of the above-mentioned compound.
• Atherosclerosis is a very important factor causative of various cardiovascular diseases, and extensive and intensive studies have been conducted with a view to suppression of the progress of atherosclerosis or regression of atherosclerosis.
• efficacy of a drug for lowering cholesterol in the serum or arterial wall is recognized.
• an ideal drug having a significant clinical effect and less liable to occurrence of an adverse effect has not been realized in the art.
• ACAT Cholesterol in foods is esterified in tunica mucosa intestini tenuis and then incorporated as chylomicron in the blood. It is known that ACAT plays an important role in the formation of a cholesterol ester in the tunica mucosa intestini tenuis or arterial wall. Therefore, it is considered that the inhibition of ACAT in the tunica mucosa intestini tenuis and the prevention of the esterification can prevent the absorption of the cholesterol, and the cholesterol level of the blood can be lowered.
• the cholesterol is accumulated as a cholesterol ester. Therefore, it is expected that the inhibition of ACAT in the arterial wall can effectively prevent the accumulation of the cholesterol ester.
• an ACAT inhibitor is considered likely to become a drug useful for treating hyperlipidemia and atherosclerosis through the prevention of the cholesterol in intestinum *** and the accumulation of the cholesterol in the arterial wall.
• urea derivatives see, for example, J. Med. Chem., vol. 29, 1131 (1986) and Japanese Unexamined Patent Publication (Kokai) Nos. 63-316761 (which corresponds to EP-A-293880 and 1-93569 (which corresponds to EP-A-297610)) and amide derivatives (see, for example, Japanese Examined Patent Publication (Kokoku) No. 63-54718 (which corresponds to U.S. Pat. No. 4,296,240 and U.S. Pat. No. 4,297,349) and Japanese Unexamined Patent Publication (Kokai) No. 63-253060 (which corresponds to U.S. Pat. No.
• Japanese Examined Patent Publication (Kokoku) No. 64-53303 which corresponds to U.S. Pat. No. 4,400,294.
• Examples of the latter compound known in the art include compounds for use as a herbicide, wherein a chloroacetamide group is bonded to the benzene ring (see Japanese Patent Unexamined Patent Publication (Kokai) No. 60-109585 (which corresponds to Derwent Abstract 85-181198)); compounds for use as a bacteriocide for agriculture and gardening, wherein a substituted phenylamide group is bonded to the benzene ring (see Japanese Unexamined Patent Publication (Kokai) No.
• 60-215680 (which corresponds to Derwent Abstract 85 -307995)); compounds for use as a starting compound for a pigment, wherein an acetylacetamide group is bonded to the benzene ring (see Japanese Examined Patent Publication (Kokoku) No. 47-7715 (which corresponds to U.S. Pat. No. 3,634,462)); compounds for use as a herbicide, wherein a substituted aryloxyisopropylamide group is bonded to the benzene ring (see Japanese Unexamined PCT Patent Publication (Kohyo) No.
• 61-501991 which corresponds to WO-A-86-2642 and EP-A-199794
• compounds for use as an antiallergic drug wherein a tetrazole group is located as an indispensable group at the 2-position and a substituted phenylamide group is bonded to the benzene ring
• Japanese Unexamined Patent Publication (Kokai) No. 2-138242 which corresponds to U.S. Pat. No. 4,780,469, U.S. Pat. No. 4,847,257 and U.S. Pat. No. 4,939,141
• compounds for use as an analgesic wherein an acetamide group is bonded to the benzene ring
• an object of the present invention is to provide a pharmaceutical composition having an ACAT enzyme inhibitory activity and capable of exhibiting an excellent therapeutic effect through a lowering in the level of cholesterol in the blood or arterial wall, a novel derivative containing a benzoxa condensed ring capable of exhibiting a significant effect and a process for producing the same.
• the present inventors have made extensive and intensive studies with a view to providing compounds significantly superior to known anti-hyperlipidemic agents and anti-atheroscleotic agents and, as a result, have unexpectedly found that certain amides or urea derivatives having a benzoxazole or 2,3-dihydrobenzofuran ring have not only a strong ACAT inhibitory activity but also strong anti-hyperlipidemic activity and anti-atheroscleotic activity, which has led to the completion of the present invention.
• the above-mentioned object of the present invention can be attained by providing a pharmaceutical composition comprising a benzoxa condensed ring compound represented by the following formula (I) or its pharmaceutically acceptable salt in an amount effective for inhibiting the action of Acyl-coenzyme A: Cholesterol Acyltransferase: ##STR4## wherein any one of P, Q, R and S is a group represented by the formula: ##STR5## with the remaining three substituents being independently a group represented by the formula --R 3 ,
• R 1 stands for a group selected from the group consisting of:
• R 9 and R 10 each independently stands for a hydrogen atom or a lower alkyl group, or may combine with each other to form a C 3 -C 7 carbon ring; and R 11 stands for a substituted or unsubstituted C 1 -C 19 alkyl, C 2 -C 19 alkenyl, C 6 -C 10 aryl, C 7 -C 19 arylalkyl or C 1 -C 19 acyl group or acyl group having a C 4 -C 19 aromatic ring, provided that the substituent when said groups are substituted is a halogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, a C 1 -C 16 alkyl, alkoxy, acylamino, monoalkylamino, alkyloxycarbonyl, acyl or acyloxy group, or a C 2 -C 26 dialkylamino group; or R 11
• A stands for a C 1 -C 12 alkylene chain
• X stands for an oxygen atom, a sulfur atom, or a group represented by the formula: ##STR7## wherein R 12 stands for a hydrogen atom or a lower alkyl or acyl group or may combine with B to form a cyclic amine, provided that, when a cyclic amine is formed, an oxygen atom, a sulfur atom, a nitrogen atom or a nitrogen atom substituted with a lower alkyl or arylalkyl group may be contained as a constituent member of the ring; and
• B stands for a substituted or unsubstituted alkyl, aryl or arylalkyl group, provided that the substituent when said groups are substituted is a halogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, a C 1 -C 12 alkyl, alkoxy, monoalkylamino, acylamino, alkyloxycarbonyl, acyl or acyloxy group, or a C 2 -C 20 dialkylamino group; and
• arylene or arylenoxy or 1 to 3 hydrogen atoms on the carbon atom may be substituted with an aryl or aryloxy group, a halogen atom or a cyano group, or the aryl portion as the substituent may be substituted with a halogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, or a lower alkyl, alkoxy, monoalkylamino, dialkylamino, acylamino, alkyloxycarbonyl, acyl or acyloxy group;
• R 2 stands for a hydrogen atom or a C 1 -C 8 alkyl group
• each R 3 independently stands for a hydrogen atom, a halogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, C 1 -C 20 alkyl, alkoxy, acylamino, monoalkylamino, alkyloxycarbonyl, acyl or acyloxy group, or a C 2 -C 26 dialkylamino group; and the alkyl portion of said groups may be interrupted by: ##STR10## wherein R 13 stands for a hydrogen atom or a lower alkyl, acyl or arylalkyl group,
• arylene or arylenoxy or 1 to 3 hydrogen atoms on the carbon atom may be substituted with an aryl or aryloxy group, a halogen atom or a cyano group, or the aryl portion as the substituent may be substituted with a halogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, a C 1 -C 20 alkyl, alkoxy, monoalkylamino, acylamino, alkyloxycarbonyl, acyl or acyloxy group, or a C 2 -C 26 dialkylamino group; and
• Z stands for a linking group which combines with an O atom, a carbon atom of the benzene ring, to which the O atom is bonded, and a carbon atom adjacent to said carbon atom to form a five-membered ring and is represented by the formula: ##STR11## wherein R 4 stands for a hydrogen atom, a C 1 -C 20 alkyl, alkenyl or alkynyl group, or a substituted or unsubstituted aryl group, provided that the substituent when the aryl group is substituted is a halogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, a C 1 -C 20 alkyl, alkoxy, monoalkylamino, acylamino, alkyloxycarbonyl, acyl or acyloxy group, or a C 2 -C 26 dialkylamino group; and
• R 5 , R 6 , R 7 and R 8 each independently stand for a hydrogen atom or a C 1 -C 20 alkyl group, or R 5 and R 6 or R 7 and R 8 combine with a carbon atom bonded thereto to form a C 5 -C 7 carbon ring; and n is 0 or 1.
• the present invention provides a novel benzoxa condensed ring compound represented by the following formula (I a ) or its pharmaceutically acceptable salt which constitutes a preferred embodiment of the above-described pharmaceutical composition: ##STR12## wherein P a , Q a and R a each independently stand for a hydrogen atom, a halogen atom, or an amino, nitro, cyano, carboxyl or hydroxyl group, a C 1 -C 20 alkyl, alkoxy, acylamino, monoalkylamino, alkyloxycarbonyl, acyl or acyloxy group, or a C 2 -C 26 dialkylamino group; and the alkyl portion of said groups may be interrupted by: ##STR13## wherein R 13 stands for a hydrogen atom or a lower alkyl, acyl or arylalkyl group,
• arylene or arylenoxy, or 1 to 3 hydrogen atoms on the carbon atom may be substituted with an aryl or aryloxy group, a halogen atom or a cyano group, and the aryl portion as the substituent may be substituted with a halogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, a C 1 -C 20 alkyl, alkoxy, monoalkylamino, acylamino, alkyloxycarbonyl, acyl or acyloxy group, or a C 2 -C 26 dialkylamino group, provided that R a stands for a group other than the hydrogen atom among the groups described above in connection with the definition of Ra; and
• R 1 , R 2 , Z and n are as defined above.
• the present invention provides the following processes for producing compounds represented by the formula (I), that is,
• R 3 and Z are as defined above, with an isocyanate represented by the following formula (III): ##STR15##
• R 1 and R 2 are as defined above, and optionally converting the reaction product to a salt;
• R 1 is as defined above, and optionally converting the reaction product to a salt
• R 1 is as defined above, and optionally converting the reaction product to a salt.
• a pharmaceutical composition comprising a compound, which partially includes a known compound, for use in the treatment of diseases developed by the action of ACAT, which compounds are unknown to have an ACAT inhibitory activity and to be useful for treating the diseases.
• treatment is used in such a concept that the compound represented by the formula (I) is used for any of therapeutic and preventive purposes.
• the term "lower” is used in such meaning that, in groups to which the term is affixed, for example, alkyl, alkenyl, alkynyl, alkoxy, acylamino, mono- or di-alkylamino, acyl and acyloxy groups and the alkyl, alkenyl or alkynyl portion of arylalkyl groups may take any of chain (straight-chain or branched) and cyclic forms having a 1 to 6 carbon atoms, unless otherwise specified.
• lower alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, cyclopropyl, cyclohexyl and cyclopropylmethyl.
• the alkyl portion is interrupted by: ##STR17## or the like is intended to mean that a suitable carbon-carbon bond of the alkyl chain may take a bonding form, such as carbon-O-carbon.
• Z in the formula combines with an oxygen atom bonded to the benzene ring, a carbon atom of the benzene ring, to which the oxygen atom is bonded, and a carbon atom adjacent to said carbon atom to form a five-membered ring, and the compounds of the formula (I) are roughly classified into groups of compounds, that is, benzoxazole derivatives (i.e., Z being a linking group represented by the formula: ##STR18## and 2,3-dihydrobenzofuran derivatives (i.e., Z being a linking group represented by the formula: ##STR19## and further classified into amide derivatives wherein each n is 0, and urea derivatives wherein n is 1.
• benzoxa condensed ring compounds belonging to the first group of compounds according to the present invention are benzoxazole derivatives represented by the following formula (I-1): ##STR20## wherein P, Q, R, S and R 4 are as defined above, and the second group of compounds are 2,3-dihydrobenzofuran derivatives represented by the following formula (I-2): ##STR21## wherein P, Q, R, S, R 5 , R 6 , R 7 and R 8 are as defined above.
• the groups Q to S are of equal significance from the viewpoint of the object of the present invention, and any one of these groups stands for a group represented by the formula: ##STR22## with the remaining substituents each independently standing for a group R 3 . Therefore, the group represented by the above-described formula may be bonded to any of the 4- to 7-positions (P, Q, R, S) in the benzene ring of the compounds represented by the formulae (I-1) and (I-2).
• compounds wherein the group represented by the above-mentioned formula is bonded to the 7-position (S) is particularly preferred from the viewpoint of the intended drug efficacy and are important also because most of them are novel compounds.
• the R 1 stands for (i) an unsubstituted cycloalkyl or cycloalkenyl group, or a cycloalkyl or cycloalkenyl group substituted at its position other than the 1-position; a group represented by the formula: ##STR23## a substituted or unsubstituted aryl group or a group represented by the formula: ##STR24## wherein the bonding group substitutes for the group: ##STR25## with the remaining groups being as defined above.
• R 1 favorable specific examples of the unsubstituted cycloalkyl or cycloalkenyl group or cycloalkyl or cycloalkenyl group substituted at its position other than the 1-position include cyclopentyl, cyclohexyl, cycloheptyl, 1-cyclohexen-1-yl, 4 -hexylcyclohexyl and 4-decyloxycyclohexyl.
• R 1 stands for a group represented by the formula: ##STR26##
• the R 9 and R 10 each independently stand for a hydrogen atom or a lower alkyl group, or combine with each other to form a C 3 -C 7 carbon ring.
• Examples of the lower alkyl group include those described above, and when the R 9 and R 10 combine with each other to form a C 3 -C 7 carbon ring, examples of the R 1 include a group represented by the following formula: ##STR27##
• favorable examples of the substituted or unsubstituted C 1 -C 19 alkyl include, besides the above-described lower alkyls, isohexyl, octyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, hexadecyl, heptadecyl, nonadecyl, icosyl, 1,1-dimethylhepthyl, 1,1-dimethylundecyl, 1,1,12,12-tetramethyltridecyl, 1-methyltridecyl, 1-decylcyclohexyl, 1-decylcyclopentyl, 1-dodecylcyclopropyl, 1-cyclohexyl-1-methylethyl, 1-ethyloctyl and 10,10-dimethylundecyl.
• examples of the C 2 -C 19 alkenyl include vinyl, allyl, butenyl, hexenyl, 8-tridecenyl, 8-heptadecenyl, 9-octadecenyl, 8,11-heptadecanedienyl, 1,1-dimethyl-8-nonenyl, cyclohexenylmethyl, 2-cyclopenten-1-yl, 2,4-cyclopentadien-1-yl, 3-cyclohexen-1-yl and 2,5-cyclohexadien-1-yl.
• R 11 when the R 11 stands for a C 6 -C 10 aryl group include phenyl, naphthyl, pyridyl and thienyl. Accordingly, in this case, specific examples of the R 1 include benzyl, 1-phenylcyclopentyl, 1-phenylethyl and 1-methyl-1-(2-pyridyl)ethyl.
• R 1 when the R 11 stands for a C 7 -C 19 aryl alkyl include 2-phenylethyl, 8-phenyloctyl, 1,1-dimethyl-11-phenylundecyl, 1-benzylcyclopentyl, (1-phenylcyclopentyl)methyl, 1,1-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)butyl, 1,1-dimethyl-7-pyridylheptyl, 2,2-diphenylethyl, 1,1-dimethyl-6-phenylhexyl, 1,1-dimethyl-7-phenylheptyl, 1,1-dimethyl-5-phenylpentyl and 1,1-dimethyl-4-phenylbutyl.
• R 11 when the R 11 stands for a C 1 -C 19 chain acyl group, C 4 -C 19 cyclic hydrocarbon acyl group or a acyl group having a aromatic ring include groups wherein a carbonyl group is bonded to a favorable group of the above-described alkyl, cyclic alkyl, chain alkenyl, cyclic alkenyl, aryl and arylalkyl groups.
• the R 11 embraces also groups wherein one or more hydrogen atoms, preferably 1 to 3 hydrogen atoms, on carbon(s) in the chain or on carbons constituting the ring are substituted with halogen atoms (for example, fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine), amino, nitro, cyano, carboxyl and hydroxyl groups and further C 1 -C 16 alkyl (as described above), alkoxy (for example, lower alkoxy, such as methoxy, ethoxy and propoxy, pentadecanoxy, decyloxy and octyloxy), acylamino (for example, lower acylamino, such as acetamide, propionylamino, butyrylamino and heptanoylamino, and lauroylamino and palmitoylamino), mono-or di-alkylamino (for example, methylamino, ethylamino, di
• R 1 having R 11 substituted with the above-described groups include 1,1-dimethyl-11-chloroundecyl, 1,1-dimethyl-7-bromoheptyl, 9-ethoxycarbonylnonyl, 1,1-dimethyl-11-hydroxyundecyl, 1,1-dimethyl-10-carboxyldecyl, 1-(4-dimethylaminophenyl)cyclopentyl, 1-methyl-1-(4-chlorophenyl)ethyl, 1-methyl-1-(4-octyloxyphenyl)ethyl, [1-(4-chloro)phenylcyclopentyl]methyl, [1-(4-dimethylamino)phenylcyclopentyl]methyl, 1,1-dimethyl-4-(4-isobutyl)phenylbutyl, 1,1-dimethyl-4-(4-hexyloxy)phenylbutyl, 1,1-d
• the R 11 may stand for a group represented by the formula --A--X--B wherein A stands for a C 1 -C 12 alkylene chain; X stands for an oxygen atom, a sulfur atom, or a group represented by the formula: ##STR28## wherein R 12 stands for a hydrogen atom or a lower alkyl or acyl group or may combine with B to form a cyclic amine, provided that, when a cyclic amine is formed, an oxygen atom, a sulfur atom, a nitrogen atom or a nitrogen atom substituted with a lower alkyl or arylalkyl group may be contained as a constituent member of the ring; and B stands for a substituted or unsubstituted alkyl, aryl or arylalkyl group.
• the alkylene in the A is a divalent group formed by further eliminating one hydrogen atom from the alkyl group, and examples thereof include those corresponding to the alkyl groups specifically described above.
• Examples of the lower alkyl and acyl groups in the R 12 include the same groups as those described above in connection with the lower alkyl group and acyl group.
• Favorable specific examples of the cyclic amine when R 12 combines with B to form a cyclic amine include 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 4-methyl-1-piperazinyl and 4-benzyl-1-piperazinyl.
• alkyl group and arylalkyl group in the B have the same meaning as the alkyl group and arylalkyl group defined above, and preferred examples thereof are also the same as those of the alkyl group and arylalkyl group described above.
• each group may be substituted in the same manner as that described above in connection with each group of R 11 .
• Favolable specific examples of the R 1 having R 11 substituted with the above-described groups include 6-isobutoxyhexyl, 6-p-chlorophenoxyhexyl, 5-p-dimethylaminophenoxypentyl, 5-isohexyloxy-1,1-dimethylpentyl, 7-isohexyloxy-1,1-dimethylheptyl, 7-isobutoxy-1,1-dimethylheptyl, 7-neopentyloxy-1,1-dimethylheptyl, 5-p -chlorophenoxy-1,1-dimethylpentyl, 6-p-chlorophenoxy-1,1-dimethylhexyl, 7-p -chlorophenoxy-1,1-dimethylheptyl, 1,1-d
• the aryl group has the same meaning as the aryl group defined above in connection with the R 11 , except that the aryl group is bonded to the carbon atom of the carbonyl group or the nitrogen atom of the group represented by the formula ##STR29## of an amide or urea portion of the formula (I-1) or (I-2).
• the substituted aryl group has a suitable substituent at the o-, m- or p-position relative to the site of bonding to the amide or urea (ureylene) portion. Preferred specific examples of these substituents include the same groups as those described above in connection with the R 11 .
• the alkyl portion may be interrupted by: ##STR30## (wherein R 13 stands for a hydrogen atom or a lower alkyl or acyl group), arylene or arylenoxy.
• R 13 stands for a hydrogen atom or a lower alkyl or acyl group
• arylene used herein is intended to mean a divalent group formed by eliminating one hydrogen atom from an aryl group, and specific examples thereof include those formed by eliminating one hydrogen atom from the aryl group specifically described above.
• the alkyl portion and aryl (or arylene) portion of these substituents as well may be substituted with one or more substituents, preferably 1 to 3 substituents, as described above connection with the R 11 .
• particularly preferred examples include p-fluorophenyl, p-decylphenyl, p-methoxyphenyl, p-isohexyloxyphenyl, p-decyloxyphenyl, p-butyrylaminophenyl, p-(N-butyl-N-methylamino, phenyl, p-valeryloxyphenyl, m-heptanoylphenyl, 4-[6-(4-chlorophenyloxy)hexyloxy]phenyl, 4-decylaminophenyl, 4-decanamidephenyl, m-decyloxyphenyl, 4-[6-(4-dimethylaminophenyloxy)-hexyloxy]phenyl, 3-chloro -4-decyloxyphenyl, 4-[6-(N-methyl-N-benzylamino)hexyloxy]phenyl and 3-di
• R 1 examples include a group represented by the formula: ##STR31## wherein P b to S b and Z have the same meaning the corresponding P a to S b and Z described above, except that one of the P b to S b stands for a linking group instead of the group represented by the formula: ##STR32##
• examples of the compound represented by the formula (I) include compounds comprising combination of the following moieties. ##STR33##
• the compound represented by the formula (I) include also a compound having such a structure that the above-described individual moieties are linked together through the divalent linking group of the ureylene group or amide group indicated at the center of the above-described structural formulae and the linking group of the left and right condensed ring moieties.
• the R 2 stands for a hydrogen atom or a C 1 -C 8 alkyl group.
• the alkyl group include, besides the above-described specific examples of the lower alkyl group, heptane, octane, cyclohexylmethyl and cyclohexylethyl.
• arylene or arylenoxy or 1 to 3 hydrogen atoms on the carbon atom may be substituted with an aryl or aryloxy group, a halogen atom or a cyano group, or the aryl portion as the substituent may be substituted with a halogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, a C 1 -C 20 alkyl, alkoxy, monoalkylamino, acylamino, alkyloxycarbonyl, acyl or acyloxy group, or a C 2 -C 26 dialkylamino group.
• these groups are the same as the meaning and specific examples of the corresponding groups described above in connection with the R 1 . More preferably, when any three of the groups P, Q, R and S stand for a group other than the group represented by the formula: ##STR36## although these three groups may be the same or different, if the R 1 stands for a group having a large number of constituent atoms (number of carbon atoms: 10 to 20), these groups preferably comprise a group having a small number of constituent atoms, for example, a hydrogen atom, a halogen atom (particularly, fluorine, chlorine or bromine), an amino, nitro, cyano, carboxy or hydroxyl group, a lower alkyl group (particularly, methyl, ethyl, propyl or isopropyl), a lower alkyloxy group (particularly, methoxy, ethoxy or propoxy), a lower acylamino group (particularly, acetamide or propionylamide), a mono
• R 1 is a group having a small number of constituent atoms (number of carbon atoms: 6 or less), it is preferred that at least one group among the P, Q, R and S except for the group represented by the formula: ##STR37## be a group having a large number of constituent atoms.
• Specific examples of the group having a large number of constituent atoms include decyloxy, decanoylamide, dodecyloxy, 4-decyloxybenzoylamide, decyl, decylamino, 2,2-dimethyldodecaneamido, 6-(4-chlorophenyl)hexyloxy, 4-(6-phenyloxy)hexyloxybenzoyl and 6-(N-methyl-N-4-chlorobenzyl)aminohexyloxy.
• the compound represented by the formula (I) wherein a group represented by the formula: ##STR38## is bonded to the 7-position (S) is particularly preferred from the viewpoint of drug efficacy.
• the 6-position (R) it is still preferred for the 6-position (R) to be a group other than a hydrogen atom from the viewpoint of the drug efficacy.
• the substituent at the 6-position it is preferred for the substituent at the 6-position to be a lower alkyl, a lower alkoxy or a halogen.
• the R 4 in the formula (I-1) stands for a C 1 -C 20 alkyl group
• specific examples of such an alkyl group are the same as those of the alkyl group described above in connection with the definition of P, Q, R and S.
• the alkenyl group is preferably a lower alkenyl group and examples thereof include vinyl, propenyl and cyclohexenyl.
• the alkynyl group is preferably a lower alkynyl group and examples thereof include ethynyl and propynyl.
• R 4 stands for a substituted or unsubstituted aryl group
• substituents are the same as those of the substituent at the site of the aryl in the definition of the R 11 and preferred examples thereof include a halogen atom, a lower alkyl, a lower alkoxy, a lower acyl, a lower alkylamino or a lower alkyloxycarbonyl.
• R 4 stands for the above-described aryl group
• favorable specific examples of the aryl group include phenyl, pyridyl, thienyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-decanoxyphenyl and 3-nitrophenyl.
• R 5 , R 6 , R 7 and R 8 in the formula (I-2) stand for a C 1 -C 20 alkyl group
• specific examples of such an alkyl group are the same as those of the alkyl group described in connection with the R 4 .
• a lower alkyl such as methyl, ethyl, propyl and isopropyl, are particularly preferred.
• These four groups may be the same or different. It is preferred that the R 5 and R 6 stand for a hydrogen atom with the R 7 and R 8 standing for a lower alkyl group.
• R 5 and R 6 or R 7 and R 8 combine with a carbon atom bonded thereto to form a C 5 -C 7 carbon ring
• favorable specific examples of such a carbon ring include C 5 -C 7 carbon rings described above in connection with the R 11 .
• the compounds having the above-mentioned formula (I) include some known compounds and novel compounds represented by the formula (Ia).
• the novel compounds can also be produced according to production processes used in the production of the known compounds. Preferably, they can be produced by a novel production process proposed as one aspect of the present invention.
• the compounds having the formula (I) can be produced by the following respective reaction schemes. ##STR209## wherein R 1 , R 2 , R 3 , Z and m are as defined above.
• reaction schemes (i) and (ii) can be practiced by reacting the corresponding amine compound represented by the formula (III) or (IV) with an isocyanate compound represented by the formula (II) or (V) in the absence or presence of a solvent.
• the amount of the amine compound and the amount of the isocyanate compound are preferably set so as to be equivalent to each other.
• the optimal amount ratio varies depending upon the reactants used. A person having ordinary skill in the art can learn the optimal amount ratio through a simple small-scale experiment.
• the amount of the isocyanate compound can be varied in the range of from 0.2 to 5 equivalents based on one equivalent of the amine compound.
• the reaction solvent may be any type of solvent so far as it has no adverse effect on the reaction.
• the solvent generally used in the reaction include halogenated hydrocarbons, such as dichloromethane and chloroform, aromatic hydrocarbons, such as benzene and toluene, ethers, such as diethyl ether and tetrahydrofuran, esters, such as ethyl acetate, and aprotic polar solvents, such as dimethylformamide and dimethylsulfoxide.
• the reaction temperature is in the range of from -20° to 150° C., preferably in the range of from room temperature to 100° C., and the reaction time is usually 72 hrs or less.
• reaction mixture may be subjected to conventional separation and purification procedure, that is, extraction, recrystallization, chromatography, etc. to isolate an intended benzoxa condensed ring compound represented by the formula (I-b) or (I-c). Further, the product can be converted to a pharmaceutically acceptable salt by a conventional method.
• the reaction corresponding to the reaction scheme (iii) is a reaction of an amine compound represented by the formula (IV) with a reactive derivative of a carboxylic acid represented by the formula (IV).
• a reaction scheme (iii) is a reaction of an amine compound represented by the formula (IV) with a reactive derivative of a carboxylic acid represented by the formula (IV).
• compounds represented by the formula (I) compounds belonging to the above-mentioned amide derivatives can be efficiently produced by this reaction.
• This reaction can be practiced according to a known reaction of an amino compound with a carboxylic acid or a reactive derivative of the carboxylic acid.
• the reactive derivative of a carboxylic acid used in the invention embraces all reactive derivatives of carboxylic acids usually known in the field of organic synthesis including acid anhydrides, acid halides and mixed acid anhydrides of the corresponding carboxylic acids.
• reaction can be practiced by reacting the amine compound with 1 to 5 equivalents of the corresponding carboxylic acid chloride or acid anhydride in the presence of a solvent.
• the reaction temperature is in the range of from -20° to 150° C., preferably in the range of from -10° to 100° C., and the reaction time is usually 72 hrs or less.
• reaction solvent examples include halogenated hydrocarbons, such as dichloromethane and chloroform, aromatic hydrocarbons, such as benzene and toluene, ethers, such as diethyl ether and tetrahydrofuran, esters, such as ethyl acetate, and aprotic polar solvents, such as dimethylformamide and dimethylsulfoxide.
• halogenated hydrocarbons such as dichloromethane and chloroform
• aromatic hydrocarbons such as benzene and toluene
• ethers such as diethyl ether and tetrahydrofuran
• esters such as ethyl acetate
• aprotic polar solvents such as dimethylformamide and dimethylsulfoxide.
• a basic amine compound for example, triethylamine, pyridine or 4-dimethylaminopyridine
• reaction mixture may be subjected to conventional separation and purification procedure, that is, extraction, recrystallization, chromatography, etc. to isolate an intended benzoxa condensed ring compound represented by the formula (I-d).
• the compound represented by the formula (I) or the compound represented by the formula (Ia) can bear, in its molecule, an amino group or a carboxyl group. Therefore, if necessary, these compounds can be converted to their acid addition salts or alkali addition salts by a conventional salt forming reaction.
• a salt forming reaction can be practiced by simply mixing the corresponding compound represented by the formula (I) with an inorganic acid or an organic acid in the absence or presence of a suitable solvent.
• the inorganic acid or organic acid used in the salt forming reaction may be any one so far as it can produce a pharmaceutically acceptable salt upon being reacted with the compound represented by the formula (I).
• the inorganic acid or organic acid include mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and carbonic acid, and organic acids, such as citric acid, malic acid, oxalic acid, tartaric acid, fumaric acid and methanesulfonic acid.
• the compound represented by the formula (I) and its pharmaceutically acceptable salt provided by the present invention have an ACAT enzyme inhibitory activity and an excellent pharmacological activity for lowering the total cholesterol and LDL levels of the blood, liver and arterial wall, which renders them useful for the suppression of the progress or regression of hyperlipidemia and atherosclerosis.
• the benzoxa condensed ring compound and its pharmaceutically acceptable salt according to the present invention can be blended with a pharmacologically acceptable carrier to provide a pharmaceutical composition.
• a pharmacologically acceptable carrier e.g., a pharmacologically acceptable carrier.
• the content of the active ingredient in the pharmaceutical composition is not particularly limited, it is usually in the range of from 5 to 70% by weight.
• the compound represented by the formula (I) and its pharmaceutically acceptable salt provided by the present invention can be orally administered.
• Examples of dosage forms of the oral preparation include a tablet, a powder, granules and a capsule.
• These dosage forms can be shaped according to a conventional method through the use of, for example, an excipient, such as lactose, starch or crystalline cellulose, a binder, such as carboxymethylcellulose, methyl cellulose or polyvinyl pyrrolidone, and a disintegrator, such as sodium alginate, sodium hydrogencarbonate or sodium laurate.
• an excipient such as lactose, starch or crystalline cellulose
• a binder such as carboxymethylcellulose, methyl cellulose or polyvinyl pyrrolidone
• a disintegrator such as sodium alginate, sodium hydrogencarbonate or sodium laurate.
• the powder and granules as well can be shaped in a similar manner.
• the capsule can be shaped by filling a capsule, such as gelatin, with a powder or granules.
• parenteral preparations include percutaneous preparations, such as a suppository, a patch and an injection.
• the dose of the compound represented by the formula (I) and its pharmaceutically acceptable salt provided by the present invention varies depending upon the severity of disease, age and sex of patient, it is usually about 1 to 500 mg/day/adult.
• reaction mixture was filtered through Celite to remove insolubles.
• the solvent was removed by evaporation to provide 154 mg of the intended title compound.
• a 50 g amount of 4-chloro-3,5-xylenol was dissolved in 50 ml of dry methanol.
• a 73.9 g amount of sodium methoxide (28% methanol solution) and 43.4 g of 3-chloro-2-methyl-1-propene was added thereto, and the mixture was heated under reflux with stirring for 28 hrs.
• the reaction mixture was cooled, the solvent was removed by evaporation, 300 ml of water was added to the residue, and the mixture was extracted with ethyl acetate (150 ml ⁇ three times).
• the organic layer was washed with a 5N aqueous sodium hydroxide solution (70 ml ⁇ two times), water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation to provide 66.6 g of a pale yellow oleaginous substance.
• a 25 g amount of anhydrous magnesium chloride was added to the oleaginous substance, and the mixture was heated at 200° C. with stirring for 24 hrs.
• the reaction mixture was cooled, 500 ml of water was added thereto, and the mixture was extracted with methylene chloride (250 ml ⁇ three times).
• the organic layer was washed with a 5N aqueous sodium hydroxide solution (100 ml), a 1N aqueous hydrochloric acid solution (100 ml) and brine in that order and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation to provide 64.8 g of a pale green oleaginous substance.
• this product was dissolved in 300 ml of acetic anhydride, and 29.09 g of nitric acid (70%) was slowly added thereto under ice cooling. The stirring was continued for additional one hour to precipitate crystal.
• the reaction was allowed to proceed at room temperature for additional 2 hr, the reaction mixture was poured into 500 ml of water, and the mixture was extracted with ethyl acetate (300 ml ⁇ 3 times). The organic layer was washed with an aqueous sodium hydroxide solution (2N, 200 ml ⁇ 2 times), water and saturated saline in that order and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation to provide pale brown crystals.
• a 20.00 g amount of 5-chloro-2,2,4,6-tetramethyl-7-nitro-2,3-dihydrobenzofuran was dissolved in 300 ml of ethyl acetate, 2.0 g of Pd-C (10%) was added thereto, and the mixture was subjected to hydrogenation at room temperature under a hydrogen gas pressure of one arm with vigorous stirring. After 24 hrs from the initiation of the hydrogenation, the consumption of hydrogen gas was about 6 liters. A 30 ml amount of triethylamine, 4.0 g of Pd-C (10%) and 100 ml of ethanol were added thereto, and the hydrogenation was continued for additional 24 hrs.
• the resultant crystal was collected by filtration, washed with a small amount of ethyl acetate and then dried to provide 14.47 g of the intended product, i.e., 7-amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran hydrochloride. The yield was 72%.
• a 171 mg amount of hexadecanecarboxylic acid chloride was added to a solution of 100 mg of 7-amino-2,2,6-trimethyl-2,3-dihydrobenzofuran and 63 mg of triethylamine in 2 ml of dichloromethane, and the mixture was stirred at room temperature for one hour.
• a 10 ml amount of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was extracted twice with 20 ml of ethyl acetate.
• the extract was dried over anhydrous magnesium sulfate, filtered, concentrated and purified by column chromatography (hexane/ethyl acetate) to provide 193 mg of the intended title compound.
• a 1.75 g amount of N-(5-amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecaneamide (486) was dissolved in 30 ml of ethanol, 4.26 g of a formaldehyde solution (37%) and 600 mg of platinum dioxide were added thereto, and the mixture was subjected to hydrogenation at room temperature. After 7 hrs from the initiation of the hydrogenation, the catalyst was removed by filtration with Celite, and the solvent was removed by evaporation. A 50 ml amount of water was added to the residue, and the mixture was extracted with ethyl acetate (30 ml ⁇ three times).
• the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate.
• the solvent was removed by distillation to provide 2.25 g of a light brown oleaginous substance.
• the oleaginous substance was purified by silica gel column chromatography (hexane/ethyl acetate) to provide 1.33 g of the intended title compound. The yield was 71.4%.
• a 452 mg amount of free base of the compound (490) prepared in Example 8 was dissolved in 3 ml of ethanol, and 1 ml of ethanol saturated with hydrochloric acid was added thereto to convert the compound to a hydrochloride. The solvent was removed by evaporation, and the resultant crystal was recrystallized from ethyl acetate to provide 313 mg of the intended title compound.
• a 410 mg amount of N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-(2,2-dimethyl-7-bromo)heptaneamide prepared according to a method described in Example 5 was dissolved in 10 ml of acetonitrile together with 139 mg of p-nitrophenol and mg of potassium carbonate, and the resultant solution 138 was heated under reflux for 2.5 hr. The solvent was removed by evaporation, 30 ml of a 5N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with 100 ml of ethyl acetate.
• the organic layer was washed with 5N sodium hydroxide, 1N hydrochloric acid, water and brine in that order and then dried over anhydrous magnesium sulfate.
• the solvent was removed by evaporation to provide 484 mg of an oleaginous substance which was then purified by silica gel column chromatography to provide 354 mg of the intended title compound.
• a 1.36 ml amount of a 1.6M n-butyl lithium hexane solution was added by portions to a solution of 304 ⁇ l of diisopropylamine in 5 ml of dry tetrahydrofuran at -78° C., and the mixture was stirred at that temperature for 30 min. Subsequently, a solution of 500 mg of 4-decyloxyacetophenone in 5 ml of dry tetrahydrofuran was added at 0° C., and the mixture was stirred at that temperature for 15 min and then at room temperature for one hour.
• 2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl isocyanate was prepared from 412 mg of 2,2,4,6-tetramethyl-7-aminodihydro -1-benzofuran according to the reference examples.
• the above-described stirred solution was added to a solution of the 2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl isocyanate in 5 ml of dry tetrahydrofuran at room temperature.
• the mixture was allowed to react for 15 hrs.
• An aqueous potassium hydrogensulfate was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
• the organic layer was washed with water and brine in that order and dehydrated over anhydrous magnesium sulfate, and the solvent was removed by distillation.
• the resultant crystal was purified by silica gel column chromatography to provide 40 mg of the intended title compound. The yield was 67.6%.
• the domestic rabbit intestinal mucosa was homogenized by using a 40 mM phosphate buffer having a pH value of 7.4 (buffer A) containing 30 mM EDTA, 50 mM KCl and 0.1M sucrose and centrifuged at 10,000 ⁇ g and a temperature of 4° C. for 30 min to provide a supernatant. The supernatant was further centrifuged at 105,000 ⁇ g and a temperature of 4° C. for one hour to provide a precipitate. The precipitate was resuspended in the buffer A to provide a microsome fraction.
• buffer A buffer having a pH value of 7.4
• a 1 %v/v dimethylsulfoxide solution of each specimen compound in a predetermined concentration was added to the buffer A containing 43 ⁇ M serum albumin and 0.5 mg/ml microsome fraction, and the mixture was heated at 37° C. for 5 min.
• test compounds had a LD 50 value of 2 g/kg or more (mouse).
• the test compound of the present invention was orally administered to the above test animals at a dose of 0.1 to 10 mg per kg of the weight once a day for three days.
• the excipient alone was administered to the control animals.
• test animals After 8 hrs from the last administration, the test animals were fasted. 16 hr after the initiation of the fasting, these test animals were slaughtered. The serum cholesterol level was measured for each animal.
• A represents the total cholesterol level of serum in the group of rats to which the test compound was administered; and B represents the total cholesterol level of serum in the control group of rats.
• a tablet containing 30 mg of the compound of Example 5 was prepared according to the following formulation.
• the present invention provides a pharmaceutical composition for use as an ACAT inhibitor and treating hyperlipidemia and atherosclerosis, which pharmaceutical composition contains a benzoxazole compound and a 2,3-dihydrobenzofuran compound. Further, it provides novel benzoxazole and 2,3-dihydrobenzofuran compounds which can be particularly usefully used in the above-described pharmaceutical composition.

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• 1991
  • 1991-12-27 ES ES92901873T patent/ES2145743T3/es not_active Expired - Lifetime
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• 1995
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